1. Field of the Invention
The invention generally relates to inhalation therapy. In particular, the invention provides methods and devices to successfully deliver and embed (deposit) in the lungs particles less than about 1 μm in diameter, by increasing and controlling the humidity of the respiratory tract.
2. Background of the Invention
Inhaled pharmaceutical aerosols are often deposited in the lungs at very low deposition efficiencies. Perhaps more significant than the quantity of drug deposited is the large inter- and intra-subject variability that is often observed with these medicinal aerosols and the associated dose delivered to the lungs. For commonly used pressurized metered dose inhalers (pMDIs), variability in lung deposition can exceed 100% (Borgstrom et al., 2006). High variability in drug deposition typically requires an increase in dose to establish consistent long-term drug effectiveness. Increasing the dosage may be acceptable for traditional inhaled medications with relatively flat dose-response curves and low systemic side effects, such as current asthma therapies. In contrast, next generation locally and systemically acting inhaled medications are expected to have narrower effective therapeutic ranges, increased side effects, and will be more expensive. For some medications, the lungs provide an advantageous delivery route based on reduced metabolism and drug degradation, adequate bioavailability, rapid onset, and needle free administration. Inhaled insulin is a primary example of a systemically acting medication with a relatively narrow therapeutic range. In order to make many next generation inhaled medications viable drug delivery alternatives, decreased inter- and intra-subject variability is of critical importance (Byron 2004).
In order to effectively deliver inhaled respiratory aerosols into the lungs, deposition in the mouth, throat and upper bronchi should be avoided. Current pulmonary delivery devices often try to minimize deposition in the mouth-throat and upper bronchi by administering particles with diameters of approximately 4 μm or less and inhaling in a prescribed manner. It has been shown that 4 μm particles have low mouth-throat and tracheobronchial deposition with a maximum pulmonary (or deep lung) deposition (Martonen 1993). Controlled inhalation waveforms can also minimize mouth-throat deposition and maximize pulmonary (or deep lung) deposition through sedimentation (Smaldone 2006). However, deposition in the mouth-throat and upper tracheobronchial region remains significant, even for current state-of-the-art aerosol delivery devices (Dalby et al., 2004; Longest et al. 2007). Perhaps more importantly, deposition in the mouth-throat (MT) is highly variable (Borgstrom et al. 2006). As a result, the dose delivered to the lungs of individual patients can vary significantly, and the exact dose received is not known.
In order to improve the delivery of medicines to the lung, a number of well known and novel generation techniques are becoming commercially available that can create relatively monodisperse nanoparticle and submicrometer aerosols without significant spray inertia effects (Gupta et al., 2003; Mazumder et al. 2006; Rabinowitz et al. 2004; Sham et al. 2004; Newth and Clark, 1989; Borgstrom et al. 2006). Submicrometer aerosols (100-1000 nm) delivered in a low inertia airstream can significantly reduce unwanted deposition in the mouth-throat region. In a recent study, Borgstrom et al. (2006) showed that reduced deposition in the highly variable MT can significantly decrease inter-subject variability in lung deposition of inhaled aerosols. However, a major problem with this delivery approach is that a high percentage of nanoparticle and submicrometer aerosols are not retained in the lungs but instead are exhaled (Heyder et al. 1986; Hofmann et al. 2001; Jaques and Kim, 2000; Morasaska et al. 1999; Morawska et al. 2005; Stahlhofen et al. 1989; Brown et al. 2002). For example, Jaques and Kim (2000) report that the total lungs retention of 100 nm aerosols can be as low as 25% without a breath hold, and Brown et al. (2002) showed that pulmonary retention of these particles is often less than 50% as these particles fail to deposit and are cleared in the exhaled air.
In order to better deliver novel pharmaceutical aerosols to the deep lung, a new generation of liquid-based drug delivery platforms is in development. These devices typically feature a decrease in initial spray or aerosol momentum, which results in a reduction in device and MT deposition. As a result of the reduced momentum approach, these delivery platforms are commonly referred to as softmist inhalers. Leading softmist inhalers were recently reviewed by Hindle (2004) and include the Respimat inhaler (Boehringer Ingelheim GmbH), the AERx inhaler (Aradigm Corp.), the Mystic inhaler (Ventaira Pharmaceuticals, Inc.), and capillary aerosol generation (CAG) (Chrysalis Technologies Inc.). Of these devices, only the Respimat inhaler is currently on the market and is only available in Europe. Clinical studies of the Respimat inhaler have indicated that a 2- to 4-fold reduction of daily doses was achieved for asthmatic patients compared with pressurized metered dose inhalers (pMDIs) (Hindle, 2004).
Computational fluid dynamic (CFD) and in vitro comparisons of a standard pMDI with the CAG system and the Respimat inhaler (Longest et al, 2008) indicated that the CAG system had relatively low and equal deposition in the inhaler mouthpiece (MP) and an attached United States Pharmacopeia (USP) standardized throat or induction port (IP), resulting in a total deposition drug loss of 20%. The Respimat inhaler had significant MP deposition (˜29%) and very low IP deposition (˜4%) resulting in a total deposition loss of 33%. In contrast, the pMDI resulted in 58% total deposition in the MP and IP. While these softmist systems appear to provide a significant improvement over standard pMDI technology, MT and extrathoracic deposition was still at an unacceptably high level. Thus, pulmonary deposition of pharmaceutical nanoparticles and submicrometer particles/droplets for both local and systemic therapeutics remains a challenge.
In summary, the problem to be solved is that, for inhalation therapy, very small particles (e.g. 1 μm and below) are preferable to larger particles because they pass through the mouth-throat area and into the deep lung more readily than do larger particles. However, such small particles are problematic because, once they reach the lung, their small size is not conducive to embedding (depositing) in the lung tissue, and they are frequently simply exhaled. In contrast, particles of about 4 μm or larger readily embed (deposit) in the lungs due to impaction, sedimentation, and other mechanisms (e.g. wall motion and electrostatic charge). However, large particles frequently fail to travel past the mouth-throat area and never reach the deep lung at all.
In order to make many next-generation inhaled medications a viable drug delivery alternative, the development of devices and methods for consistent targeted lung delivery and decreased inter- and intra-subject variability are of critical importance. In particular, devices and methods that deliver aerosolized submicrometer and nanometer sized particles past the mouth-throat and into the targeted areas of the respiratory tract under conditions which cause or allow the particles to embed (deposit), for example, in the deep lung, would be highly advantageous.